The present invention relates to orally administrable pharmaceutical compositions, and specifically relates to compositions that are designed to reduce the potential for improper administration of medications and their use in a non-indicated or non-prescribed manner. The present invention can comprise any drug, and it is especially useful with medications that are subject to abuse, such as drugs affecting the central nervous system. For example, the present invention is particularly useful for pain medications, medications to reduce or eliminate anxiety attacks, stimulants and sleeping pills. With these general types of drugs, there is the potential of abuse and improper administration that may result in drug overdose, addiction, suboptimal efficacy, and/or death.
Opioid agonists are substances that act by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract. When these drugs attach to certain opioid receptors in the brain and spinal cord, they can effectively block the transmission of pain messages to the brain. Opioid analgesics such as oxycodone, morphine, oxymorphone, hydrocodone and hydromorphone are successful and therapeutically useful pain medications. Opioids undergo phase 1 metabolism by the cytochrome P450 (CYP) pathway, phase 2 metabolism by conjugation, or both, as described in Smith H, “Opioid Metabolism,” Mayo Clin. Proc., 2009; 84(7):613-624.
Morphine, also known as (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, is an example of a potent opioid analgesic used in the treatment of acute, chronic, and severe pain. Major metabolites of morphine include morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), hydromorphone, normorphine (NM) and minor metabolites such as morphine-3,6-diglucuronide, morphine-3-ethereal sulfate, normorphine-6-glucuronide, and normorphine-3-glucuronide. Morphine-6-glucuronide (M6G), a major metabolite of morphine, is formed by glucuronidation. M6G and morphine both demonstrate analgesic activity.
Oxycodone, also known as (5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioid analgesic used for the treatment of pain. Major metabolites of oxycodone include noroxycodone, a oxycodol, 13 oxycodol, oxymorphone, a oxymorphol, 13 oxymorphol, noroxymorphone, a noroxycodol, 13 noroxycodol, noroxymorphone, 14-hydroxydihydrocodeine, and 14-hydroxydihydromorphine. Oxymorphone and noroxycodone are the most commonly known major metabolites of oxycodone.
Oxymorphone, also known as 14-hydroxydihydromorphinone and 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one, is an opioid analgesic used for the treatment of pain. Major metabolites of oxymorphone include oxymorphone-3-glucuronide and 6-hydroxy-oxymorphone.
Hydrocodone, which is also known as 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one, is an opioid analgesic used for the treatment of pain. Major metabolites of hydrocodone include norhydrocodone and hydromorphone.
Hydromorphone, which is also known as 4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one, is an opioid analgesic. Major metabolites of hydromorphone include hydromorphone-3-glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide.
Codeine, which is also known as a (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol, is an opioid used for its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties. Major metabolites of codeine include codeine-6-glucuronide (C6G), norcodeine, hydrocodone, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine.
Central nervous stimulants are often used to increase mental alertness, and they can results in feelings of exhilaration and energy. Examples of such drugs include amphetamines such as methylphenidate, dextroamphetamine, and lisdexamfetamine.
Methylphenidate, which is also known as methyl phenyl(piperidin-2-yl)acetate, is a drug often used for treatment of narcolepsy, attention-deficit/hyperactivity disorder, and depression. Major metabolites of methylphenidate include but are not limited to ethylphenidate, ritalinic acid (α-phenyl-2-piperidine acetic acid), hydroxymethylphenidate, and hydroxyritalinic acid.
Dextroamphetamine, which is also known as (2S)-1-phenylpropan-2-amine, is a drug used for treatment of narcolepsy, attention-deficit/hyperactivity disorder, and depression. Major metabolites of dextroamphetamine include but are not limited to 4-hydroxyamphetamine, benzoic acid, phenylacetone, hippuric acid, 4-hydroxynorephedrine, and norephedrine.
Lisdexamfetamine, also known as lisdexamfetamine, is another stimulant. It is a prodrug of phenethylamine and amphetamines such as dextroamphetamine.
Benzodiazepines are commonly used to treat anxiety. Examples of benzodiazepines include, but are not limited to alprazolam, lorazepam, and diazepam.
Alprazolam, which is also known as 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, is a short acting anxiolytic. Major metabolites of alprazolam include, but are not limited to 4-hydroxyalprazolam and α-hydroxyalprazolam.
Lorazepam, which is also known as (RS)-7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one, is an anxiolytic agent having intermediate duration of action. Major metabolites of lorazepam include, but are not limited to, 3-O-phenolic glucuronide and lorazepam glucuronide.
Diazepam, which is also known as 7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2(3H)-one, is a commonly used anxiolytic. Major metabolites of diazepam include, but are not limited to desmethyldiazepam, esmethyldiazepam, oxazepam, and temazepam.
While pain medications, medications to reduce or eliminate anxiety attacks (psychotherapeutic drugs), stimulants and sleeping pills can be safe, effective, and therapeutically useful when administered properly, such drugs are susceptible to abuse. Examples of such compositions include but are not limited to ROXICODONE® (oxycodone tablets), OXYCONTIN® (oxycodone tablets), DILAUDID® (hydromorphone tablets), OPANA® and OPANA ER® (oxymorphone tablets), MS CONTIN® (morphine tablets), CONCERTA®, METHYLIN®, RITALIN®, RITALIN LA®, and EQUASYM KL® (methylphenidate tablets and capsules), FOCALIN® (dexmethylphenidate capsules), ADDERALL®, DEXEDRINE®, and DEXTROSTAT® (dextroamphetamine tablets and capsules), VYVANSE® (lisdexamfetamine capsules), ATIVAN® (lorazepam), XANAX® (alprazolam), and VALIUM® (diazepam).
A sense of euphoria or “high” can be experienced with high serum concentrations of these drugs. Individuals seeking to abuse these drugs will often tamper with oral dosage forms containing the drugs to achieve this “high.” For example, a large amount of tablets can be placed in a liquid to form a solution, and abusers either consume the liquid or more often filter and inject the solution. These tablets can also be crushed into a powder or small particle sizes and snorted intranasally. Nasal insufflation, which is another term for the inhalation of substances through the nose, is a common and harmful practice among abusers. Long-term practice of nasal insufflation can result in permanent damage to nasal tissue and increased incidence of toxicity and overdose. There is a need in the art for pharmaceutical compositions which minimize the ability for abuse, and when administered properly, provide an adequate and effective amount of drug.
It is an object of the present invention to provide a pharmaceutical composition that reduces the potential for improper administration drugs but which, when administered as directed through oral administration, is capable of delivering a therapeutically effective dose to a subject. In particular, the present invention addresses the need for an orally administrable drug product which, compared to conventional formulations, decreases the ability of an individual to achieve a “high” or euphoria effect through injection or insufflation.